Pharmacokinetics of Favipiravir in Critically Ill Patients With COVID‐19

Abstract

Since December 2019, a novel coronavirus (severe acute respiratory syndrome‐coronavirus 2 (SARS‐CoV‐2)) infection has been rapidly spreading worldwide and causing the respiratory illness, coronavirus disease 2019 (COVID‐19). The antiretroviral drug favipiravir (FPV) has been experimentally used for COVID‐19 treatment since March 2020 in Japan. However, the pharmacokinetics of FPV in critically ill patients is unknown. We measured the serum concentration of FPV using high‐performance liquid chromatography in patients with severe COVID‐19 who were admitted to the intensive care unit and placed on mechanical ventilation. The patients were administered 1,600 mg of FPV twice daily on day 1, followed by 600 mg twice daily from day 2 to day 5 (or more if needed). Suspensions of FPV tablets were administered through a nasogastric tube. Seven patients were enrolled in this study. Forty‐nine blood samples were obtained from the eligible patients to evaluate FPV concentration. The FPV trough (after 8–12 hours) concentrations of most samples were lower than the lower limit of quantification (1 µg/mL) and half‐maximal effective concentration (9.7 µg/mL) against SARS‐CoV‐2 previously tested in vitro. FPV trough concentration in critically ill patients was much lower than that of healthy subjects in a previous clinical trial, which is a cause for great concern. Further study is required to determine the optimal strategy for treatment of patients with severe COVID‐19.

Favipiravir at high doses has potent antiviral activity in SARS-CoV-2−infected hamsters, whereas hydroxychloroquine lacks activity

“…However, it is not known whether the lung penetration in humans is similar to that in hamsters, limiting a possible extrapolation of our results. On the other hand, it has been reported that the trough concentrations (after 8 h to 12 h) in critically ill COVID-19 patients are lower than those in healthy persons and do not reach the in vitro obtained EC 50 values against SARS-CoV-2 (41,42). This unfavorable PK profile of favipiravir has been observed previously in Ebola virus-infected patients (40).…”

Favipiravir versus other antiviral or standard of care for COVID-19 treatment: a rapid systematic review and meta-analysis

“…Selective reporting may have been a problem in Chen’s study [ 19 ] because of the limited observation time frame. It is important to determine the appropriate dose and duration of treatment with FVP because low dose therapy is found to be a bad prognostic factor for clinical improvement and widespread variations in treatment duration among studies and lack of effective plasma concentrations of drug in critically ill patients [ 13 , 14 ]. Due to the early evidence of potential benefits shown by this drug in clinical improvement as well as imaging improvement, it is necessary to conduct large-scale prospective, double-blind randomized controlled trials or wait for the result of ongoing studies to come.…”

Favipiravir versus other antiviral or standard of care for COVID-19 treatment: A rapid systematic review and meta-analysis

“…Selective reporting may have been a problem in Chen's study because of the limited observation time frame. It is important to determine the appropriate dose and duration of treatment with FVP because low dose therapy is found to be a bad prognostic factor for clinical improvement and widespread variations in treatment duration among studies and lack of effective plasma concentrations of drug in critically ill patients [11,12]. Because of the early evidence of potential bene ts shown by this drug in clinical improvement as well as imaging improvement, it is necessary to conduct large scale prospective, double-blind randomized controlled trials to further increase the power of the study and eliminate biases so that de nitive advice for treatment can be given in the coming days.…”